Chronic pain affects a large number of Americans, costing an estimated $600 billion annually. In particular, temporomandibular joint disorder (TMD), a complex chronic pain condition influenced by biological, psychological, environmental and social factors affects about 6% of the population. Recent studies suggest that genetics plays an important role in pain sensitivity, modulation and susceptibility to the development of chronic pain and TMD. Individual chronic pain experience is highly variable; some people are mildly affected, while others suffer debilitating dysfunction. Individuals also vary substantially n their responses to therapeutic interventions; for some, pharmacological treatments are highly efficacious while in others only modest reductions in pain occur. Up to 50% of the variability in clinical pain outcomes has been shown to be secondary to expectancy-induced analgesia, defined as the reduction in pain in an individual that results from his or her perception of the therapeutic intervention. In other words, patients' expectancies can modulate the individual pain experience, processing and response to pain treatments. Therefore, better understanding of the genetic effects on expectancy-induced analgesia and the variability in proneness to activate endogenous inhibitory systems is critical to optimize pain treatments. We developed a novel comprehensive genetic, behavioral and imaging approach to study the role of genetic variations on behavioral, psychological and neuronal mechanisms of expectancy-induced analgesia in patients with TMD. We address the following specific aims: 1. Test the hypothesis that variants in candidate genes are associated with expectancy-induced analgesia predicting chronic orofacial pain endophenotypes; 2. Test the hypothesis that individual psychological traits are unique modulators of the complex genetic moderation of expectancy-induced analgesia, regardless of the severity of the disease; and 3. Test the hypothesis that variations in the specific (identified) genes predict expectancy-induced analgesia and related neuronal changes in the prefrontal and limbic areas. The identified genotypes will serve as important markers to predict subjective (e.g. pain reports) and objective (e.g. neuronal) responses to expectancy-induced analgesia while controlling for modulatory effects of distinct personalities. We anticipate: a) to provide a new framework to study the pharmacogenomics of chronic orofacial pain, b) to identify genetic markers and mechanisms that can be used to develop new therapeutic targets and strategies and ultimately, c) to determine which patients are most likely to respond to specific treatments.